The objective of the proposed research is to define the association between an identified polymorphism in the gene encoding the heme biosynthetic pathway enzyme, coproporphyrinogen oxidase (CPOX), an atypical porphyrinogenic response to mercury (Hg), Hg exposure, and Hg-mediated neurobehavioral effects in adults and children. The long-term goal is to reduce or prevent neurological deficits potentially caused by low-level environmental Hg exposure by identifying genetic factors that may alter susceptibility to Hg toxicity and by defining the efficacy of an established biomarker of Hg exposure to identify suscepible individuals. The specific aims of the proposed research are to (1) define the association between the CPOX polymorphism and the atypical porphyrinogenic response to Hg in children, (2) define the potential effects of the CPOX polymorphism on the association between Hg exposure and neurobehavioral performance deficits in children, (3) define the potential effect of the CPOX polymorphism on Hg body burden and measures of recent and chronic Hg exposure in adults, (4) compare the the biochemical properties of the gene products of wildtype and polymorphic CPOX, and (5) define potential effects of additional candidate genes that are known to affect neurological function (e.g., BDNF, 5-HTT, COMT, TOD2) on the association between Hg exposure and neurobehavioral performance in adults and children. We will accomplish these objectives using established genetic analytical techniques, along with comprehensive, longitudinal neurobehavioral and neurological test results, in well-established cohorts of adults and children with prolonged, low-level Hg exposure comparable to that experienced by persons residing near Superfund hazardous waste sites. Knowledge gained from this project will improve public understanding about the effects of low-level Hg exposure on human health, the possible influence of genetic factors on Hg toxicity, and how Hg exposure and toxicity can be reduced or prevented. These studies directly address Superfund Program needs by identifying a biomarker that could be used assess exposure, potential health risks, and altered susceptibility to Hg toxicity in adults and children who reside near Hg-contaminated hazardous waste sites.